Central chemoreceptors monitor brain CO2-pH and provide an essential component of the drive to breathe, operating with peripheral chemoreceptors that rapidly sense arterial O2 and CO2-pH. Asthma is a common often life-threatening disorder associated with changes in PaO2, PaCO2, and the drive to breathe, yet little is known about circuits that link chemoresponsive brain regions to the respiratory network for motor pattern generation or the roles of these pathways during acute asthma attacks. The goal of this project is to identify functional connectivity among three brainstem chemoresponsive regions and the pontomedullary network for breathing, and to test model-based predictions on network mechanisms for regulating the drive to breathe during hypocapnia and acute challenge-evoked exacerbations in an established sensitized animal model of asthma. Aim 1 addresses the hypothesis that central chemoresponsive neurons in the retrotrapezoid nucleus/parafacial respiratory group, the rostral medullary raphi, and nucleus of the solitary tract regulate the respiratory motor pattern generator through multiple pathways, including circuits shared by baroreceptor and peripheral chemoreceptor reflexes. Aim 2 targets mechanisms of central chemoreceptor modulation of peripheral chemoreceptor influences on breathing during hypocapnia. Hypocapnia and hypoxemia frequently accompany acute asthma attacks. Reduced chemosensitivity to hypoxia is a likely contributing factor in patients with near-fatal episodes. Thus, Aim 3 pursues the hypothesis that chemoreceptor reflex circuit mechanisms are appropriated and reconfigured during antigen challenge-evoked exacerbations. The experimental approach combines advanced multi-electrode array technologies, computational methods for network analysis and predictive modeling, circuit interrogation by selective activation of central and peripheral chemoreceptors and other challenges. Expected outcomes include a new conceptual framework on respiratory network architecture, evidence for adaptive chemoreceptor reflex circuit mechanisms that control breathing during hypocapnic hypoxia, and the first network-scale assessment of identified central and peripheral reflex circuit functions during acute antigen-challenge evoked episodes in an animal model system of asthma.